2. Academic Validation
  3. Hypoxia-driven heterogeneous expression of α5 integrin in glioblastoma stem cells is linked to HIF-2α

Hypoxia-driven heterogeneous expression of α5 integrin in glioblastoma stem cells is linked to HIF-2α

  • Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167471. doi: 10.1016/j.bbadis.2024.167471.
Mélissa Messé 1,  Chloé Bernhard 2,  Sophie Foppolo 2,  Lionel Thomas 3,  Patrice Marchand 3,  Christel Herold-Mende 4,  Ahmed Idbaih 5,  Horst Kessler 6,  Nelly Etienne-Selloum 7,  Charles Ochoa 8,  Uttam K Tambar 8,  Mohamed Elati 9,  Patrice Laquerriere 3,  Natacha Entz-Werle 10,  Sophie Martin 2,  Damien Reita 11,  Monique Dontenwill 12
Affiliations

Affiliations

  • 1 UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; UMR7178 CNRS, Hubert Curien Multidisciplinary Institute, Strasbourg University, 67000 Strasbourg, France.
  • 2 UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France.
  • 3 UMR7178 CNRS, Hubert Curien Multidisciplinary Institute, Strasbourg University, 67000 Strasbourg, France.
  • 4 Division of Neurosurgical Research, Department of Neurosurgery, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 5 Sorbonne University, AP-HP, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, F-75013 Paris, France.
  • 6 Institute for Advanced Study, Department Chemie, Technical University Munich (TUM), Lichtenbergstr. 4, 85747 Garching, Germany.
  • 7 UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; Pharmacy department, Institut de Cancérologie Strasbourg Europe (ICANS), 67200 Strasbourg, France.
  • 8 Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, United States.
  • 9 Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 - CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille F-59000, France.
  • 10 UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; Pédiatrie Onco-Hématologie-Pédiatrie III, Strasbourg University Hospital, 67091 Strasbourg, France.
  • 11 UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France; Department of Cancer Molecular Genetics, Laboratory of Biochemistry and Molecular Biology, University Hospital of Strasbourg, 67200 Strasbourg, France.
  • 12 UMR7021 CNRS, Tumoral Signaling and Therapeutic Targets, Strasbourg University, Faculty of Pharmacy, Illkirch, France. Electronic address: monique.dontenwill@unistra.fr.
PMID: 39154793 DOI: 10.1016/j.bbadis.2024.167471
Abstract

Despite numerous molecular targeted therapies tested in glioblastoma (GBM), no significant progress in patient survival has been achieved in the last 20 years in the overall population of GBM patients except with TTfield setup associated with the standard of care chemoradiotherapy. Therapy resistance is associated with target expression heterogeneity and plasticity between tumors and in tumor niches. We focused on α5 Integrin implicated in aggressive GBM in preclinical and clinical samples. To address the characteristics of α5 Integrin heterogeneity we started with patient data indicating that elevated levels of its mRNA are related to hypoxia pathways. We turned on glioma stem cells which are considered at the apex of tumor formation and recurrence but also as they localize in hypoxic niches. We demonstrated that α5 Integrin expression is stem cell line dependent and is modulated positively by hypoxia in vitro. Importantly, heterogeneity of expression is conserved in in vivo stem cell-derived mice xenografts. In hypoxic niches, HIF-2α is preferentially implicated in α5 Integrin expression which confers migratory capacity to GBM stem cells. Hence combining HIF-2α and α5 Integrin inhibitors resulted in proliferation and migration impairment of α5 Integrin expressing cells. Stabilization of HIF-2α is however not sufficient to control Integrin α5 expression. Our results show that AHR (Aryl Hydrocarbon Receptor) expression is inversely related to HIF-2α and α5 Integrin expressions suggesting a functional competition between the two transcription factors. Collectively, data confirm the high heterogeneity of a GBM therapeutic target, its induction in hypoxic niches by HIF-2α and suggest a new way to attack molecularly defined GBM stem cells.

Keywords

Glioma stem cells; HIF-2α; Hypoxia; α5 integrin.

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